Specific Features of Cerebral Venous Thrombosis Associated With Iron Deficiency Anemia

Anonymized data supporting the study's findings are available from the corresponding author upon reasonable request. The present study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline. 16 Approval for data collection was obtained from local ethic committee. All patients were informed of the use of their clinical data for research purposes and included under a nonopposition procedure in accordance with national regulations; written informed consent was not required. Among consecutive patients with CVT enrolled in the prospective Lariboisière university hospital cohort between 1998 and 2023, we analyzed those presenting with moderate or severe IDA at admission. Anemia was defined according to the World Health Organization criteria ( https://www.who.int/publications/i/item/WHO‐NMH‐NHD‐MNM‐11.1 ), with moderate anemia defined as hemoglobin <11 g/dL in men and nonpregnant women, and <10 g/dL in pregnant women; severe anemia as hemoglobin <8 g/dL in men and nonpregnant women, and <7 g/dL in pregnant women. Iron deficiency was defined by microcytic anemia—mean corpuscular volume <80 fL—and ferritin <15 mg/L, or, when applicable, transferrin saturation 1.7 mg/L. Patients with other potential causes of microcytic anemia (eg thalassemia major or intermedia, inflammation), were excluded. Clinical and laboratory data at admission were systematically recorded. Clinical data included demographics (age and sex), medical history, time from symptoms onset to CVT diagnosis—classified as acute (≤2 days), subacute (3–30 days), or chronic (>30 days)—and clinical presentation, categorized into 3 subtypes: isolated headache, isolated intracranial hypertension, and focal syndrome (deficit or seizure). Delayed neurological deterioration was recorded. Thrombotic risk factors beyond anemia were documented, as well as the mechanism of IDA. The mechanism of IDA was classified based on previously published criteria 17 into categories such as increased iron demand (eg, pregnancy), environmental factors (insufficient intake from poverty, malnutrition, or diet), decreased absorption, chronic blood loss from the gastrointestinal or genitourinary tract, drug‐related causes, genetic conditions, or iron‐restricted erythropoiesis. Management during hospitalization, including admission to intensive care, anticoagulation therapy, blood transfusion, and iron supplementation, was also recorded. Laboratory data included hemoglobin levels, mean corpuscular volume, ferritin level, and, when applicable, transferrin saturation or soluble transferrin receptor, platelet count, C‐reactive protein, and thrombophilia screening. The latter involved testing for protein C, protein S, and antithrombin deficiency, c.*97G>A (prothrombin G20210A) variant of F2 gene, c.1601G>A; P .Arg534Gln (also known as R506Q or Factor V Leiden mutation) variant of F5 gene, methylenetetrahydrofolate reductase ( MTHFR ) C677T variant and plasma homocystein (μmol/L) and antiphospholipid antibodies. CVT diagnosis was confirmed using magnetic resonance imaging/magnetic resonance angiography, computed tomography venography/angiography, or conventional angiography if needed. The location of the thrombus, the number of involved venous sinus, and the presence of associated parenchymal lesions such as infarction or hemorrhage were documented. Clinical outcome was assessed at discharge and 1 year after CVT using the modified Rankin Scale (mRS). Disability was classified into 3 categories: excellent outcome (mRS score 0–1), favorable outcome (mRS score 2), and dependence or death (mRS score 3–6). Venous recanalization was evaluated using follow‐up neuroimaging at 3 to 6 months and 1 year, and categorized as absent, partial, or complete. Patients with CVT and IDA were compared with those without anemia from the Lariboisière cohort with CVT (1998–2023). Individuals with other causes of anemia were excluded. Demographics and main clinical, radiological, and outcome data were compared between patients with CVT and IDA (both overall and severe cases) and those without anemia. Additional analyses were conducted based on hemoglobin levels using the same data set. Categorical variables were expressed as the number (percentage) and quantitative variables as mean±SD or median (interquartile range) in cases of nonnormal distribution. Normal data distributions were assessed graphically and using Shapiro–Wilk test. Demographics and main clinical and radiological features of patients with CVT and IDA were compared with those of patients with CVT without anemia using Student t tests (or Mann–Whitney U test for non‐Gaussian distribution) for quantitative variables and using chi‐square tests (or Fisher's exact test in case of expected cell frequency <5) for categorical variables. The strength of between‐group differences was assessed by calculating the standardized differences with their 95% CI; absolute values of 0.2, 0.5, and 0.8 were interpreted as small, moderate, and large differences. To account for multiple testing, a false discovery rate controlling procedure was applied and associations were considered significant if the false discovery rate‐adjusted P value was ≤0.05. Associations of IDA status with excellent functional outcome at discharge and at 1 year were investigated using logistic regression models, without and with adjustment for prespecified confounders (age, sex, and intraparenchymal hemorrhage) 3 as well as for all patient characteristics associated with IDA at a P value<0.05 in univariate analyses. Odds ratio (OR) and its 95% CI for patients with CVT and IDA versus without were reported as effect size. Given that only 2 men had IDA (compared with 62 women), we performed a sensitivity analysis excluding men from the study population (see Figures  S2 and S3 ). All analyses were repeated by considering severe IDA status or the hemoglobin levels. Association of hemoglobin levels with demographics and main clinical and radiological features were investigated using Spearman rank correlation coefficient, or Student t test or 1‐way ANOVA, depending on the variables studied. ORs of excellent functional outcome associated with hemoglobin levels were expressed per 1‐SD decrease, after checking the log‐linearity assumption using restricted cubic spline function. Statistical testing was conducted at the 2‐tailed α‐level of 0.05 without imputation of missing values. Data were analyzed using the SAS software version 9.4 (SAS Institute, Cary, NC).

Between 1998 and 2023, 64 out of 616 patients (10.4%) in the cohort with CVT presented with moderate or severe IDA and were included in the study. Characteristics of patients with CVT and IDA are presented in Table  1 . Most patients were female (96.9%). The mean age at CVT diagnosis was 35 years (SD 12.6), with ages spanning from 16 to 59 years. Symptom onset was mostly acute (28.1%) or subacute (62.5%), with a median time from onset to diagnosis of 7 days (interquartile range, 2–15). Headache was the most common symptom, reported in 63 patients (98.4%), isolated in 18 patients (28.1%) and 13 patients (20.3%) presented with isolated intracranial hypertension. Focal syndrome, including deficit or seizure, was observed in 33 patients (51.6%), altered consciousness occurred in 15 patients (23.4%). Baseline Characteristics of Patients With Cerebral Venous Thrombosis and Iron Deficiency Anemia Values are no./total no. (%) or median (25th to 75th percentiles) unless otherwise specified (number of patients in case of missing data). During the acute phase, 9 patients (14.1%) experienced delayed neurological deterioration. At admission, the mean±SD hemoglobin level was 8.1±1.4 g/dL, with severe anemia documented in 27 patients (42.2%). The mean corpuscular volume was 65.8±8.0 fl. Mean±SD platelet level was 425±172×10 9  G/L with thrombocytosis (ie, platelet count >450×10 9  G/L) reported in 24 patients (38.1%). Neuroimaging revealed multiple involved sinuses and veins in 37 patients (57.8%), with the transverse sinus most frequently affected (51 patients, 79.7%). Cortical veins were involved in 21 patients (32.8%). Parenchymal lesions were detected in 35 patients (54.7%), including venous infarction in 21 patients (32.8%) and intraparenchymal hemorrhage in 17 (26.6%) (Table  1 ). The cause of IDA was identified in 60 patients (94.0%), most commonly chronic genital blood loss (45 patients, 75.0%) secondary to uterine fibroids or adenomyosis. Other causes included gastrointestinal bleeding (7 patients, 11.7%), environmental or insufficient intake (12 patients, 20.0%), and decreased absorption (12 patients, 20%) (Table  1 ). Additional thrombotic risk factors were identified in 41 patients (64%), with oral estroprogestative contraceptives use being the most common (26 patients, 41.9%) (Table  1 ). Thrombophilia screening was positive in 7 patients (10.9%), revealing heterozygous F2 G20210A variant in 1 patient, heterozygous Factor V Leiden in 1, protein C deficiency in 1, primary antiphospholipid syndrome in 2 (persistent positive anticardiolipin IgG antibodies in 1 and persistent lupus anticoagulant and positive antiphosphatidylserine IgG in 1) and hyperhomocysteinemia with homozygous MTHFR C677T in 2 patients. Among the 64 patients with CVT and IDA, 11 (17.2%) required intensive care unit admission. All patients received anticoagulation therapy, initially with heparin: unfractionated heparin in 6 patients, low molecular weight heparin in 39, unfractionated heparin followed by low molecular weight heparin in 17, and unspecified in 2. This was followed by vitamin K antagonists in 43 patients (67.2%) and direct oral anticoagulants in 15 patients (23.4%). Antiepileptic drugs were administered to 23 patients (35.9%). Twenty‐two patients (34.4%) received antiedematous treatment, almost exclusively acetazolamide. Endovascular thrombectomy was performed in 1 patient (1.6%), and neurosurgery in 5 patients (7.8%). Iron supplementation was given to 61 patients (95.3%), including intravenous iron therapy in 23 patients (35.9%). Blood transfusions were required in 22 patients (34.4%), with a median of 2 red blood cell units administered. Among patients with genital blood loss‐related IDA, 16 (25.8%) underwent gynecological surgery, including 3 (4.8%) requiring emergency intervention. Gonadotropin‐releasing hormone analogs were initiated in 9 patients (14.1%) (Table  2 ). Treatment of Patients With Cerebral Venous Thrombosis and Iron Deficiency Anemia Values are no./total no. (%). As shown in Figure  1 , at discharge, excellent outcome (ie, mRS score 0–1) was achieved in 64.1% of patients (n=41), favorable outcome (mRS score 2) in 20.3% (n=13), and dependence or death (mRS score 3–6) in 15.6% (n=10). One patient died within the initial hospitalization. At 1 year, excellent outcome was achieved in 83.3% of patients (n=50), favorable outcome in 11.7% (n=7), and dependence or death in 5.0% (n=3). Four patients had insufficient follow‐up. Neuroimaging performed at 3–6 months (n=50) showed partial (n=38) or complete (n=11) recanalization in 49 patients (98.0%). At 1 year (n=38), recanalization was observed in 37 patients (97.0%). mRs indicates modified Rankin Scale. Following the extraction of patients with CVT and IDA from the Lariboisière cohort with CVT (1998–2023) (n=64) and the exclusion of patients with anemia from other causes (n=50), a total of 502 patients with CVT without anemia were eligible for comparison. As shown in Figure  2A , female sex was more represented in patients with CVT and IDA (96.9%) compared with those without anemia (73.3%) ( P <0.001). Patients with CVT and IDA also have more frequently an added thrombotic risk factor (64.1% versus 31.4%, P <0.001). Focal syndrome was more frequent in patients with CVT and IDA (51.6%) than in those without anemia (42.0%) ( P =0.15) (Figure  2A ). This difference reached statistical significance in patients with severe IDA (63.0% versus 41.8%, P =0.032) (Figure  2B ). Severe IDA appeared to be associated with a higher prevalence of altered consciousness (40.7% versus 18.3%, P =0.004) even when hemoglobin level was analyzed (Table  S1 ); only a weak positive correlation with age was found (r=0.16) and a significant difference in clinical presentation, with a lower hemoglobin level for patients with CVT with focal syndrome ( P =0.011). Parenchymal lesions were significantly more frequent in patients with CVT and IDA (54.7%) than in those without anemia (35.3%) ( P =0.0025), with venous infarction being significantly more common in patients with CVT and IDA (32.8% versus 14.5%, P =0.0002), irrespective of the severity of anemia. After false discovery rate correction, female sex, additional thrombotic risk factors, and the presence of parenchymal lesions remained significantly associated with both IDA and severe IDA. Venous infarction also remained significantly associated with overall IDA (Figure  2 ). A , CVT without vs with IDA; ( B ) CVT without vs with severe IDA. CVT indicates cerebral venous thrombosis; and IDA, iron deficiency anemia. *Significant at 0.05 level after adjustment for false discovery rate. Regarding clinical outcome, patients with CVT and IDA (or severe IDA) were less likely to achieve excellent outcomes than patients without anemia, both at discharge and at 1 year; however, after adjustment, the association was significant only for severe anemia at discharge (Figure  3 and Figure  S1 ). Notably, the adjusted OR per 1‐SD decrease of hemoglobin was 0.77 (95% CI, 0.59–1.01) for excellent outcome at discharge and 0.73 (95% CI, 0.53–0.99) at 1 year. In sensitivity analysis restricted to women, similar estimates were observed (Figures  S2 and S3 ). Adjusted ORs were calculated using logistic regression including age, sex, presence of at least 1 thrombotic risk factors other than anemia, venous infarction, and intraparenchymal hemorrhage as covariables. For hemoglobin level, ORs were expressed per 1‐SD decrease. CVT indicates cerebral venous thrombosis; and OR, odds ratio.

None.

In this large cohort, we described the association between IDA and CVT and showed that the population profile was predominantly represented by women, a finding that likely reflects the primary identified cause of IDA in this group (ie, chronic blood loss from the genital tract, mainly due to fibroids and adenomyosis). Two thirds of patients had at least 1 additional thrombotic risk factor, most commonly oral contraceptive use, reinforcing the strong female predominance in this cohort. Notably, the prevalence of IDA in our cohort with CVT is higher than in general stroke (2.5%–5%), 18 , 19 reinforcing a possible specific link between ID and venous thrombosis. Another distinctive characteristic of our study population was the higher clinical severity at admission, particularly in patients with severe IDA. Focal neurological deficits were more frequently observed in patients with IDA, paralleling the higher frequency of parenchymal lesions and venous infarctions seen on neuroimaging. Despite a more severe presentation at admission and, in cases of severe IDA, at discharge, the 1‐year outcomes were not significantly different from those of patients without anemia. These findings provide a more nuanced interpretation of previous studies that have linked anemia with poorer outcomes in patients with CVT. 13 , 14 , 15 Two key factors may account for this discrepancy. First, clinical outcome may be influenced not only by anemia itself but also by its underlying cause. In our cohort, IDA was primarily due to “benign” gynecological conditions in young women (eg, fibroids, adenomyosis), whereas prior studies included patients with anemia from diverse causes, including malignancies, which are known to worsen prognosis. Second, the proactive IDA diagnosis and management during hospitalization may have contributed to improve outcomes at 12 months, limiting the impact of initial severity on functional outcome. In addition to standard anticoagulation therapy, targeted treatment of IDA was systematically implemented, including iron supplementation (administered intravenously in one third of cases), blood transfusions, and specific interventions addressing the underlying cause of anemia. Notably, gynecological surgery (such as myomectomy or hysterectomy) was performed in a substantial proportion of patients, sometimes as an emergency procedure, whereas gonadotropin‐releasing hormone analogs were initiated in selected cases. In contrast to other cardiovascular conditions, such as acute myocardial infarction, where blood transfusion is recommended to achieve a hemoglobin level ≥10 g/dL, 20 there are no clear guidelines regarding the management of anemia in patients with stroke or CVT. Interestingly, one study demonstrated improved outcomes following packed red blood cell transfusion in patients with anemia (<12.1 g/dL in women and <13.1 g/dL in men) and intracerebral hemorrhage. 21 A more recent study also indicated better neurological outcome in patients with acute brain injury and anemia when treated with a liberal transfusion strategy (triggered by hemoglobin <9 g/dL) compared with a restrictive strategy (triggered by hemoglobin <7 g/dL). 22 Our findings support the proposition of an aggressive treatment approach for IDA upon admission, favoring intravenous iron supplementation and considering transfusion for severe anemia. The pathophysiological link between anemia and CVT remains a subject of debate. In IDA, the presence of associated thrombocytosis, as observed in our population, represents a key mechanism that may enhance platelet activation, promote thrombus formation, and increase thrombus volume. 23 , 24 Experimental studies have demonstrated that these prothrombotic effects are reversible following iron repletion, supporting a causal relationship between IDA‐related thrombocytosis and thrombosis. 24 Several other mechanisms have been proposed to explain the association between anemia and CVT. One hypothesis is that anemia can induce a hyperkinetic circulatory state, leading to endothelial dysfunction and promoting thrombus formation. 25 Recent studies support the association of chronic anemia with systemic endothelial activation, characterized by increased expression of adhesion molecules such as ICAM‐1 (intercellular adhesion molecule‐1) and VCAM‐1 (vascular cell adhesion molecule‐1), and elevated inflammatory markers. 26 Additionally, altered red blood cells properties in IDA (such as reduced deformability) may also contribute to endothelial activation. 27 Given their anatomical characteristics (ie, such as smaller size relative to the dural sinuses), cortical veins may be particularly susceptible to the thrombotic burden, potentially explaining their higher involvement in our cohort compared with literature reports, where they are implicated in ∼15%–17% of CVT cases. 3 , 4 , 28 In turn, this may contribute to the increased incidence of parenchymal lesions observed in our study. These findings further underscore the critical importance of early IDA correction to optimize patient outcomes. Finally, our study revealed a high rate of recanalization in patients with IDA compared with the literature. 29 This may be attributed to the underlying pathophysiological mechanisms we discussed and the rapid correction of anemia during hospitalization. The major strength of the study lies in the prospective nature of our cohort, which allowed for the collection of comprehensive hemoglobin levels without missing data, even though IDA was not the initial focus. Access to detailed laboratory data, including anemia causes, with minimal missing information, further strengthens the robustness of our findings. However, our study has some limitations. First, this was a single‐center study, making selection bias unavoidable. Second, although we systematically assessed and treated IDA, the impact of these interventions on long‐term outcomes remains uncertain. Finally, no formal sample size calculation was done, and we caution that we could not exclude that some associations could be overlooked due to a lack of adequate statistical power. Given the width of CIs, only large associations can be ruled out.

In conclusion, our findings underscore the importance of recognizing and managing IDA as a modifiable risk factor in CVT, particularly in young women. Future multicenter studies are needed to validate our findings, better characterize the interplay between IDA and CVT, and determine the impact of early IDA management on long‐term outcomes in patients with CVT.

None.

Table S1 Figures S1–S3 STROBE Checklist